The goal of our Program Project is to discover the biological transformations that occur in the brain during the perimenopausal transition that can result in phenotypes predictive of risk for development of AD pathology. In Project 3, our specific emphasis is the neuroprotective actions of ovarian hormones on AD pathogenesis. Menopause is characterized in part by depletion of ovarian hormones. We hypothesize that menopause induces neural changes that attenuate the established protective effects of estradiol and progesterone against pathways associated with AD pathogenesis. Menopause is also linked with increases in body weight and adiposity that often lead to obesity and metabolic syndrome, conditions that are established risk factors for the development of AD. Significantly, adiposity and obesity are not only regulated by ovarian hormones, but also are known to impair bioenergetics and increase inflammation. Thus, perimenopause results in adverse changes to both ovarian hormones and adiposity, which we theorize interact cooperatively in the promotion on AD pathogenesis via their effects on bioenergetic, inflammatory, and AD pathways. To investigate these relationships, we propose three specific aims that are highly collaborative across all cores and projects. Specific Aim 1: Prodromal phenotypes in rat and mouse models of human perimenopause/menopause. We will characterize the effects of reproductive aging on AD genes and pathways using rodent models of perimenopause. Specific Aim 2: How does obesity interact with perimenopause in the regulation of bioenergetic, inflammatory, and Alzheimer pathways? We will determine the effects of diet-induced obesity on AD pathways and how they interact with reproductive aging. Specific Aim 3: Perimenopausal hormone intervention: timing and efficacy for protection against Alzheimer pathways. We will define the window of opportunity for delivering estradiol and progesterone hormone therapy that effectively protects against AD pathways in our rodent models of perimenopause using both rats and the 3xTg-AD mice.